特发性肺纤维化组织中脂肪酸代谢相关基因的生物信息学分析及实验验证

doi:10.13481/j.1671-587X.20260110

吉林大学学报(医学版) ›› 2026, Vol. 52 ›› Issue (1): 93-104.doi: 10.13481/j.1671-587X.20260110

特发性肺纤维化组织中脂肪酸代谢相关基因的生物信息学分析及实验验证

林潇¹,周梦²,林帆¹,姚秀娟³()

^1.福州大学附属省立医院老年医学科，福建福州 350001
^2.福州大学附属省立医院风湿免疫科，福建福州 350001
^3.福州大学附属省立医院呼吸与危重症医学科，福建福州 350001

收稿日期:2025-04-08 接受日期:2025-05-31 出版日期:2026-01-28 发布日期:2026-02-24
通讯作者: 姚秀娟 E-mail:yxj@fjmu.edu.cn
作者简介:林潇（1987-），男，福建省福州市人，副主任医师，医学硕士，主要从事肺纤维化的基础方面的研究。
基金资助:
福建省科技厅科技创新联合资金项目(2024Y9024);福建省科技厅自然科学基金（青年创新）项目(2023J05229)

Bioinformatics analysis and experimental validation of fatty acid metabolism-related genes in idiopathic pulmonary fibrosis tissue

Xiao LIN¹,Meng ZHOU²,Fan LIN¹,Xiujuan YAO³()

^1.Department of Geriatric Medicine，Affiliated Provincial Hospital，Fuzhou University，Fuzhou 350001，China
^2.Department of Rheumatology and Immunology，Affiliated Provincial Hospital，Fuzhou University，Fuzhou 350001，China
^3.Department of Respiratory and Critical Care Medicine，Affiliated Provincial Hospital，Fuzhou University，Fuzhou 350001，China

Received:2025-04-08 Accepted:2025-05-31 Online:2026-01-28 Published:2026-02-24
Contact: Xiujuan YAO E-mail:yxj@fjmu.edu.cn

摘要/Abstract

摘要：

目的采用生物信息学方法鉴定特发性肺纤维化（IPF）组织中的核心脂肪酸代谢相关基因（FAMRGs），并通过实验验证上述基因是否在IPF组织和正常肺组织中呈显著差异表达。方法从基因表达综合数据库（GEO）下载2个IPF基因芯片数据集，包括GSE47460数据集和GSE150910数据集，人类基因综合数据库（GeneCards）中筛选FAMRGs，GEO2R工具筛选出GSE47460数据集中IPF组织和正常肺组织的差异表达基因（DEGs），通过对DEGs与FAMRGs绘制韦恩图，获得差异表达的FAMRGs。采用仙桃学术工具对上述基因进行富集分析，STRING数据库分析并导入Cytoscape软件建立蛋白-蛋白相互作用（PPI）网络图并筛选出关键FAMRGs，通过GSE150910数据集对上述基因的表达水平进行验证，并绘制受试者工作特征（ROC）曲线，筛选出核心FAMRGs。采用CIBERSORT网站分析在IPF组织中核心FAMRGs表达水平与免疫细胞浸润的关系。选取18只健康雄性SD大鼠，随机分为对照组、IPF组和吡非尼酮组，每组6只。IPF组和吡非尼酮组大鼠气管内注射博来霉素以制备肺纤维化模型，对照组大鼠气管内注射等量生理盐水。造模成功后，对照组和IPF组大鼠以10 mL·kg^-1·d^-1生理盐水灌胃，吡非尼酮组大鼠以10 mL·kg^-1·d^-1吡非尼酮混悬液灌胃，药物干预14 d后处死，取出肺组织。采用Masson染色观察3组大鼠肺组织纤维化程度，Western blotting法检测3组大鼠肺组织中的FAMRGs蛋白表达情况。结果共筛选出182个差异表达的FAMRGs。基因本体论（GO），上述FAMRGs主要涉及激素调节、对肽类物质的反应、信号受体激动剂活性和细胞因子活性等功能。京都基因与基因组百科全书（KEGG），上述FAMRGs主要富集于白细胞介素17（IL-17）信号通路、晚期糖基化终末产物-晚期糖基化终末产物受体（AGE-RAGE）信号通路和缺氧诱导因子-1（HIF-1）信号通路等。从PPI网络中鉴定出前10位关键FAMRGs，通过GSE150910数据集的验证，确定基质金属蛋白酶3（MMP3）、分泌型磷蛋白1（SPP1）和胰岛素样生长因子1（IGF1）为IPF组织中核心FAMRGs，与正常肺组织比较呈明显高表达（P<0.001）。免疫浸润分析，在IPF组织中浆细胞、调节性T细胞、M0型巨噬细胞和静息肥大细胞的表达明显上调（P<0.05），静息CD4记忆T细胞、静息自然杀伤（NK）细胞、单核细胞、嗜酸性粒细胞和中性粒细胞的表达则明显下调（P<0.05），Spearman相关性，在IPF组织中SPP1与M0型巨噬细胞表达水平呈正相关关系（P<0.001），与单核细胞表达水平呈负相关关系（P<0.001）。Masson染色，与对照组比较，IPF组大鼠肺组织中胶原纤维沉积明显增多；与IPF组比较，吡非尼酮组大鼠肺组织中胶原纤维沉积明显减少。Western blotting法，与对照组比较，IPF组大鼠肺组织中的MMP3、SPP1和IGF1蛋白表达水平明显升高（P<0.05）；与IPF组比较，吡非尼酮组大鼠肺组织中的MMP3、SPP1和IGF1蛋白表达水平明显降低（P<0.05）。结论 MMP3、SPP1和IGF1为IPF组织中的核心FAMRGs，可作为未来IPF治疗的潜在靶点。

关键词: 特发性肺纤维化, 脂肪酸代谢, 生物信息学, 免疫浸润, 吡非尼酮

Abstract:

Objective To identify the core fatty acid metabolism-related genes （FAMRGs） in idiopathic pulmonary fibrosis （IPF） tissue using bioinformatics methods， and to experimentally verify whether these genes are significantly differentially expressed in IPF tissue and normal lung tissue. Methods Two IPF gene chip datasets， including the GSE47460 dataset and the GSE150910 dataset， were downloaded from the Gene Expression Omnibus （GEO） database； FAMRGs were screened from the Human Gene Comprehensive Database （GeneCards） database； the GEO2R tool was used to screen the differentially expressed genes （DEGs） between IPF tissue and normal lung tissue in GSE47460 dataset； Venn diagram was drawn between the DEGs and FAMRGs to obtain the differentially expressed FAMRGs. Xiantao Academic Tool was used to perform functional enrichment analysis on the above genes； the STRING database was used for analysis and Cytoscape software was used to establish a protein-protein interaction （PPI） network and screen the key FAMRGs； the GSE150910 dataset was used to verify the expression levels of the above genes， and receiver operating characteristic （ROC） curves were plotted to screen the core FAMRGs. The CIBERSORT database was used to analyze the relationship between the core FAMRGs and immune cell infiltration in IPF tissue. Eighteen healthy male SD rats were selected and randomly divided into control group， IPF group， and pirfenidone group， with 6 rats in each group. The rats in IPF group and pirfenidone group were intratracheally injected with bleomycin to establish the pulmonary fibrosis model， and the rats in control group were intratracheally injected with an equal volume of normal saline. After successful modeling， the rats in control group and IPF group were given 10 mL·kg^-1·d^-1 normal saline by gavage， and the rats in pirfenidone group were given 10 mL·kg^-1·d^-1 pirfenidone suspension by gavage； after 14 d of drug intervention， the rats were sacrificed and lung tissue was taken. Masson staining was used to observe the degree of fibrosis in lung tissue of the rats in the three groups； Western blotting method was used to detect the expression of FAMRGs proteins in lung tissue of the rats in three groups. Results A total of 182 differentially expressed FAMRGs were screened. The Gene Ontology （GO） analysis results showed that the above FAMRGs were mainly involved in functions such as hormone regulation， response to peptide substances， signaling receptor agonist activity， and cytokine activity. The Kyoto Encyclopedia of Genes and Genomes （KEGG） analysis results showed that the above FAMRGs were mainly enriched in signaling pathways such as interleukin-17 （IL-17） signaling pathway， advanced glycation end products-receptor for advanced glycation end products （AGE-RAGE） signaling pathway， and hypoxia-inducible factor-1（HIF-1） signaling pathway. Ten key FAMRGs were identified from the PPI network. Through validation with the GSE150910 dataset， matrix metalloproteinase 3 （MMP3）， secreted phosphoprotein 1 （SPP1）， and insulin-like growth factor 1 （IGF1） were determined as the core FAMRGs in IPF tissue， and their expressions were significantly higher compared with normal lung tissue （P<0.001）. The immune infiltration analysis results showed that in IPF tissue， the expressions of plasma cells， regulatory T cells， M0 macrophages， and resting mast cells were significantly up-regulated （P<0.05）， while the expressions of resting CD4 memory T cells， resting natural killer （NK） cells， monocytes， eosinophils， and neutrophils were significantly down-regulated （P<0.05）； the Spearman correlation analysis results showed that in IPF tissue， the expression level of SPP1 was positively correlated with the expression level of M0 macrophages （P<0.001）， and negatively correlated with the expression level of monocytes （P<0.001）. The Masson staining results showed that compared with control group， the collagen fiber deposition in lung tissue of the rats in IPF group was significantly increased； compared with IPF group， collagen fiber deposition in lung tissue of the rats in pirfenidone group was significantly decreased. The Western blotting results showed that compared with control group， the expression levels of MMP3， SPP1， and IGF1 proteins in lung tissue of the rats in IPF group were significantly increased （P<0.05）； compared with IPF group， the expression levels of MMP3， SPP1， and IGF1 proteins in lung tissue of the rats in pirfenidone group were significantly decreased （P<0.05）. Conclusion MMP3， SPP1， and IGF1 are the FAMRGs in IPF tissue and can serve as potential targets for future IPF treatment.

Key words: Idiopathic pulmonary fibrosis, Fatty acid metabolism, Bioinformatics, Immune infiltration, Pirfenidone

中图分类号:

R563

林潇,周梦,林帆,姚秀娟. 特发性肺纤维化组织中脂肪酸代谢相关基因的生物信息学分析及实验验证[J]. 吉林大学学报(医学版), 2026, 52(1): 93-104.

Xiao LIN,Meng ZHOU,Fan LIN,Xiujuan YAO. Bioinformatics analysis and experimental validation of fatty acid metabolism-related genes in idiopathic pulmonary fibrosis tissue[J]. Journal of Jilin University(Medicine Edition), 2026, 52(1): 93-104.

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ID	Term	Count	P	Gene
hsa04657	IL-17 signaling pathway	11	8.51E-07	MMP1, CCL11, MMP3, CCL7, IL-6, FOS, LCN2, MUC5B, PTGS2, IL-13, CSF3
hsa00980	Metabolism of xenobiotics by cytochrome P450	9	9.86E-06	CYP2F1, GSTA2, CYP3A5, ADH4, UGT1A6, CYP2A7, CYP1B1, ADH7, ALDH3A1
hsa04933	AGE-RAGE signaling pathway in diabetic complications	10	1.14E-05	EDN1, AGER, VEGFA, COL4A3, EGR1, IL-6, COL3A1, TGFB3, IL-1α, SERPINE1
hsa04066	HIF-1 signaling pathway	10	2.45E-05	EDN1, NOS2, TEK, TF, VEGFA, IL-6, IGF1, PFKFB3, SERPINE1, PDK1
hsa00982	Drug metabolism - cytochrome P450	8	4.13E-05	GSTA2, CYP3A5, ADH4, UGT1A6, CYP2A7, ADH7, FMO1, ALDH3A1

特发性肺纤维化组织中脂肪酸代谢相关基因的生物信息学分析及实验验证

Bioinformatics analysis and experimental validation of fatty acid metabolism-related genes in idiopathic pulmonary fibrosis tissue

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